A. Field of the Invention
The present invention relates to methods for milling and preparing powders, changing the surface properties of a drug particle, and compositions produced thereby. In some embodiments, the process described utilizes jet-milling with a cold stream of gas mixed with air and powders. More specifically the cold gas stream is nitrogen gas mixed with liquid nitrogen, under controlled conditions. The resulting milled particle size can range from less than 200 nanometers to greater than one micrometer, depending on the processing conditions and application. The process described can be used to form a stable powder of a single material, a mixture of materials and/or excipients, as well as modify the surface of particles to improve the dispersion and/or stability of a powder intermediate or final product. The powder compositions produced thereby possess improved properties including, but not limited to, improved flow and dispersibility, stability, resistance to moisture, dissolution/release profiles, and/or bioavailabilities. This process, and the compositions produced, provide significant advantages in the manufacture of pharmaceutical particle delivery systems (PDS), as well as biomedical, diagnostic, and chromatography particulate compositions, where insoluble compounds or sensitive particles, such as proteins or vaccines, are involved that would be degraded using more rigorous, high temperature processing conditions.
B. Description of the Related Art
There has been substantial effort in the last decade to produce drug particles from 100 nanometers to a few microns because of their improved dissolution properties (especially with insoluble drugs) and ability to be absorbed more efficiently. Solid nanoparticle formulations are typically made by wet-milling and subsequent packaging into vials or lyophilization, and may contain large amounts of stabilizers that inhibit aggregation and growth of the particle during drying or storage. Dry-milling of inhaled dry-powder formulations in fluid energy or jet mills, such as for inhaled asthma drugs, has been described, but not under reduced temperature. Use of pure nitrogen gas (non-cryogenic) while jet-milling (U.S. Pat. No. 5,354,562) formulations for inhalation has been shown to reduce insoluble contaminants and inactive fractions in the milled product.
Jet mills are shear or pulverizing machines in which the particles to be milled are accelerated by gas flows and pulverized by collision. There are a number of different types of jet mill designs, such as double counterflow (opposing jet) and spiral (pancake) fluid energy mills. Gas and particle flow may simply be in a spiral fashion, or more intricate in flow pattern, but essentially particles collide against each other or against a collision surface. In counterflow fluid-energy or jet mills, i.e., mills of the character described whereby two particle-entraining streams are directed against one another, the carrying gas may be derived from steel bottles or flasks and is permitted to flow through two venturi nozzles in parallel into the fluid-energy or jet mill chamber, the reduced pressure developed in the venturi nozzle together with increased velocity causes the granular or coarse-particle material to be entrained with high speed along a trajectory counter to the trajectory of the particles of the other stream. When two particle streams moving at high velocity and with high kinetic energy in opposite directions collide, the impact releases this kinetic energy in the form of energy of breakdown whereby the structure of the granules is altered or destroyed. Glancing collisions have a similar effect and are also valuable because they provide a mutual abrasion and rounding of the particles. Air or hot steam are generally used as the milling gas.
Inherently brittle materials that are not affected by moderate heat rise are usually easy to grind under ambient conditions with commercial impact or shear milling equipment. Other less brittle materials may be adequately cooled during grinding by simply passing air or another gas through the grinding mill along with the material to be ground. Many substances, for example, plastic, are difficult or impossible to mill to a fine grain size because of their toughness. However, when such tough materials are exposed to cold, they become brittle, which improves their milling properties. A single propellant gas is cooled before introduction into a jet mills, for example, in U.S. Pat. No. 3,897,010. Cooling the complete propellant gas flow makes it possible to mill materials that could not be milled under normal conditions in jet mills. However, in spite of intensive cooling, and in spite of the self-cooling effect of the cooled propellant gas flow as a result of its expansion, the attainable improvement of the milling properties leaves a great deal to be desired. Although fine grain sizes can be achieved, this is only possible at an excessively high consumption of time and energy. Typically such a gas-cooled system makes economic sense only if the material can be ground at 0° C. or higher, less then that requiring significant cooling equipment and energy consumption.
More resilient or elastic materials and those that are particularly sensitive to heat rise, including many chemicals, pharmaceuticals, food, powder coatings, and organic dyes, can require significant precooling and grinding at 0° C. or below. In this case, the materials require processing in a cryogenic grinding system that's cooled by a cryogen, a refrigerant that produces a low-temperature environment in the system. The low-temperature environment chills the material below the glass-transition point, the temperature at which the material becomes brittle and glass-like, to facilitate grinding in a mill that applies impact or shear, such as a jet-mill.
Cryogenic jet-milling is a well-suited size reduction technique for elastic, resilient materials likely to be damaged or destroyed by heat, i.e. pharmaceuticals. It is known that the rate of dissolution of a particulate drug can increase with increasing surface area, i.e., decreasing particle size. Consequently, methods of making finely divided drugs have been studied and efforts have been made to control the size and size range of drug particles in pharmaceutical compositions. Pharmaceuticals, such as oral nanoparticle delivery systems, may be prepared without using wet processes such as with fine grinding media, as described in U.S. Pat. No. 6,592,903 and related patents, or homogenization, as described in U.S. Pat. No. 6,835,396 and related patents. Using cryogenic conditions while milling for these and other resilient or heat-sensitive materials controls heat build-up, which can protect and enhance final product properties, produce finer particles/improve nanoparticle size yield, and increase the production rate.
Delivery of discrete nanoparticles and microparticles have been investigated for inhalation, nasal, topical, ocular, buccal, and injectable delivery. Pulmonary delivery of low molecular-weight drugs, peptides/proteins, and gene-therapy agents for local or systemic therapies presents unique formulation challenges. Efficient and reproducible drug deposition to central sections of the lung, such as glucocorticoids for asthma therapies, and peripheral sections of the lung for systemic delivery, such as insulin for patients with diabetes, is difficult because of limitations involved in aerosolization, stability, and clearance of micron-sized liquid droplets and powders. Currently available delivery systems for the inhalation of drugs include metered-dose inhalers (MDI's), dry-powder inhalers (DPI's), and nebulizers. Inhaled delivery of small molecule drugs including beta-agonists, such as albuterol, and glucocorticoids, such as budesonide and fluticasone propionate, have been used clinically for decades where small portions (20-200 μg) of the packaged dose are deposited in the desired portions of the lung (typically 5-10%). New non-invasive inhaled therapies being developed, such as peptides and proteins intended for systemic delivery, have distinctive physicochemical properties that further complicate efficient delivery, as well as may require large ‘lung-doses’ in the order of 2-20 mg, i.e. insulin. Dry-powder formulations of macromolecules are of particular interest for inhaled therapies since their stability is higher in the dry-state. Unfortunately, current formulations and inhalers are inefficient with fine particle doses of 5-20% of total emitted dose and high dose-to-dose variability. Spray-dried insulin particles aerosolized in an active pressured inhaler device, such as described in U.S. Pat. No. 5,997,848 and related patents, are able to provide >50% respirable fraction, although only 5-15% of insulin is absorbed systemically. Improved inhaler devices and particle processing techniques are needed to efficiently deliver therapeutics through the pulmonary route.
Final dosage forms that incorporate drug particle compositions, such as a tablet, inhaled powder, or a solution for injection, typically contain bulking agents and/or surface stabilizers that may be chemically or physically attached on the surface, or more simply physically mixed, to disperse effectively. Oral tablets and capsules, as well as inhaled dry-powders, typically incorporate at least one pharmaceutically acceptable water-soluble or water-dispersible excipient. Common agents include carriers, dispersants, or generally excipients, which require additional mixing to obtain biological activity upon storage and administration of a final dosage form. Because of the inherently high electrostatic forces present in nanoparticles and microparticles, direct mixing with carrier particles, such as in dry-powder inhaled formulations, may be inefficient and result in low quality final products. For this reason, manufacturing of nanometer and micrometer size drug particles that include excipients before the bulk mixing phase to improve the dispersion properties are of great interest to produce an improved final product. An example of a drug particle microencapsulation process is also described in U.S. Pat. No. 6,406,745 which may be used to microencapsulate drug particles efficiently without the use of solvents or high temperatures, which may damage the drug molecule or activity.
Particle formation methods by crystallization, solvent evaporation, and granulation are practiced in the pharmaceutical, biotechnology, and food industry. Particle size is often reduced through secondary processing such as milling, while particle size may be increased through granulation and spray-coating techniques. Unfortunately, for small nanoparticles and microparticles used for inhaled, nasal, injectable, oral, and topical delivery, the resulting particles are highly charged and very cohesive, reducing their manufacturability and delivery efficiency and subsequent therapeutic efficacy. Therefore, what is needed are improved, cost-effective methods for preparing particles that do not suffer these limitations, and that are useful in preparing particles with distinct particle sizes and surface properties to obtain a superior final product.